Volume 114

Number 10

15 May 1991

Annals of Internal Medicine ARTICLES

Low-Dose Aspirin Therapy for Chronic Stable Angina A Randomized, Placebo-Controlled Clinical Trial Paul M. Ridker, MD; JoAnn E. Manson, MD; J. Michael Gaziano, MD; Julie E. Buring, ScD; and Charles H. Hennekens, MD

Objective: To evaluate the efficacy of low-dose aspirin in the primary prevention of myocardial infarction among patients with chronic stable angina. Design: A randomized, double-blind, trial. Patients: The study included 333 men with baseline chronic stable angina but with no previous history of myocardial infarction, stroke, or transient ischemic attack who were enrolled in the Physicians' Health Study, a trial of aspirin among 22 071 male physicians. Intervention: Patients were randomly assigned to receive alternate-day aspirin therapy (325 mg) or placebo and were followed for an average of 60.2 months for the occurrence of myocardial infarction, stroke, or cardiovascular death. Results: During follow-up, 27 patients had confirmed myocardial infarctions; 7 were among the 178 patients with chronic stable angina who received aspirin therapy and 20 were among the 155 patients who received placebo (relative risk, 0.30; 95% CI, 0.14 to 0.63; P = 0.003). While simultaneously controlling for other cardiovascular risk factors in a proportional hazards model, an overall 87% risk reduction was calculated (relative risk, 0.13; CI, 0.04 to 0.42; P < 0.001). For the subgroup of patients with chronic stable angina but no previous coronary bypass surgery or coronary angioplasty, an almost identical reduction in the risk for myocardial infarction was found (relative risk, 0.14; CI, 0.04 to 0.56; P = 0.006). Of 13 strokes, 11 occurred in the aspirin group and 2 in the placebo group (relative risk, 5.4; CI, 1.3 to 22.1; P = 0.02). No stroke was fatal, but 4 produced some long-term impairment of function. One stroke, in the aspirin group, was hemorrhagic. Conclusion: Our data indicated that alternate-day aspirin therapy greatly reduced the risk for first myocardial infarction among patients with chronic stable angina, a group of patients at high risk for cardiovascular death (P < 0.001). Although our results for stroke were based on small numbers, they suggested an apparent increase in frequency of stroke with aspirin therapy; this finding requires confirmation in randomized trials of adequate sample size. Annals of Internal Medicine. 1991;114:835-839.

Of the five million Americans who have coronary heart disease, more than 600 000 die each year, half from acute myocardial infarction and half from complications of chronic ischemic heart disease (1). Patients with chronic stable angina are at particularly high risk; their cardiovascular disease mortality rates range between 2% and 10% per year, depending on their degree of exercise intolerance and the number of obstructed coronary vessels (2, 3). Although antianginal therapy with nitrates (4, 5), beta blockers (6, 7), and calciumchannel antagonists (8-10) reduces symptoms and increases exercise tolerance, none of these agents has been shown to reduce the risk for first myocardial infarction among patients with this clinical syndrome. Low-dose aspirin therapy irreversibly inhibits platelet aggregation (11, 12) and reduces the risk for thrombotic vascular disease in various categories of patients (13). In particular, aspirin prevents myocardial infarction, stroke, and vascular death in patients with previous histories of myocardial infarction, stroke, transient cerebral ischemia, and unstable angina pectoris (14). These reductions in the risks for myocardial infarction, stroke, and vascular death are also clearly apparent when low-dose aspirin therapy is given during suspected evolving myocardial infarction (15). In primary prevention, aspirin, 325 mg on alternate days, reduces the risk for first myocardial infarction by 44% in apparently healthy men (16, 17). At present, however, no data from randomized trials of low-dose aspirin therapy in the primary prevention of myocardial infarction among patients with chronic stable angina have been reported. The Physicians' Health Study, a randomized, doubleblind, placebo-controlled trial of aspirin (325 mg on alternate days), enrolled 333 men with a history of chronic stable angina but without previous myocardial infarction, stroke, or transient ischemic attack. In this report, we examine the effect of low-dose aspirin therapy on the development of vascular disease among this group of high-risk patients with chronic stable angina pectoris.

From the Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts. For current author addresses, see end of text.

Patients and Methods The participants in and the methods of the Physicians' Health Study have been previously described (16, 17). Briefly, ©1991 American College of Physicians

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22 071 male physicians in the United States, ranging in age from 40 to 84 years at entry and without a previous history of myocardial infarction, stroke, or transient cerebral ischemia, were assigned at random, using a 2 x 2 factorial design, to one of four treatment groups: aspirin and beta carotene, aspirin and beta carotene placebo, aspirin placebo and beta carotene, or aspirin placebo and beta carotene placebo. A total of 11 037 men were assigned to receive aspirin (Bufferin, Bristol-Myers, New York, New York), 325 mg on alternate days, and 11 034 men were assigned to receive aspirin placebo. Before randomization, all participants completed health status questionnaires that requested information about chronic stable angina. Every 6 months for the first year and annually thereafter, participants were sent brief questionnaires about compliance, side effects, and the development of relevant clinical outcomes. At randomization, 333 participants had a history of chronic stable angina. Of these, 178 were assigned to receive active aspirin, and 155 were assigned to receive aspirin placebo. These participants were followed for an average of 60.2 months for the development of myocardial infarction, stroke, and cardiovascular death. Of reported cardiovascular end points, over 97% were confirmed or refuted through reviews of medical records by an end points committee of physicians who were blinded to treatment assignment. The diagnosis of myocardial infarction was confirmed by World Health Organization criteria (18). Nonfatal stroke was defined as a typical neurologic deficit that was sudden or rapid in onset, that lasted more than 24 hours, and that was attributable to a cerebrovascular event. Strokes were further classified according to the severity of the residual impairment at the time of hospital discharge and according to probable cause (ischemic or hemorrhagic) on the basis of medical records, computed tomographic scanning, and the judgment of the neurologist on the end points committee. Deaths from cardiovascular causes were documented by convincing evidence of a cardiovascular mechanism from all available sources, including death certificates, hospital records, and, for deaths occurring outside the hospital, observers' impressions. Statistical Analysis For myocardial infarction, intention-to-treat analyses were done using all incident cases occurring after randomization. Although based on small numbers, similar analyses were done Table 1. Baseline Characteristics

for incidence of stroke, cardiovascular death, and death from all causes. All analyses were adjusted for age (5-year categories) and for beta carotene treatment assignment. For each end point, relative risks were calculated as the ratio of the number of events per person-year of observation in the aspirin group divided by corresponding rates in the placebo group. Multivariate relative risks were derived from proportional hazards models that simultaneously controlled for age and beta carotene assignment as well as for baseline characteristics, including cigarette smoking (never, past, current), systolic and diastolic blood pressure, elevated serum cholesterol level, diabetes mellitus (yes or no), parental history of infarction before the age of 60 years (yes or no), body mass index, alcohol use (> daily or rarely or never),and vigorous exercise (^ once per week or < once per week). For each relative risk, a two-sided P value and a 95% confidence interval (CI) were calculated. Results The baseline characteristics of the 333 participants with chronic stable angina pectoris showed no important differences (P > 0.05) between the aspirin and placebo groups for age, blood pressure, body mass index, exercise frequency, and the percentages with hypercholesterolemia, a smoking history, or a parental history of myocardial infarction. Participants with stable angina who were assigned to aspirin therapy had an increased frequency of diabetes mellitus (14% compared with 7%; P = 0.03) (Table 1). During follow-up, 27 participants had confirmed myocardial infarctions; 7 were among the 178 participants with chronic stable angina who received aspirin therapy (4%), and 20 were among the 155 participants who received placebo (13%) (age- and beta carotene-adjusted relative risk, 0.30; 95% CI, 0.14 to 0.63; P = 0.003) (Table 2). While simultaneously controlling for other cardiovascular risk factors in a proportional hazards model, an overall 87% reduction in the risk for first

of 333 Participants with Chronic Stable Angina in the Physicians'

Characteristic

Mean age, y Patients with hypertension, %% Mean systolic blood pressure, mm Hg Mean diastolic blood pressure, mm Hg Patients with high cholesterol levels, %§ Mean cholesterol level, mmol/L Patients with diabetes mellitus, % Mean body mass index, kglm2 Patients with parental history of myocardial infarction, %|| Cigarette smoking, % Never Past Current Exercise frequency > once/week < once/week Alcohol use, % Daily Rarely or never

Aspirin Group (* = 119)t 63.6 38.1 132.5 80.3 14.9 5.9 14.1 25.4 25.6

± 9.3 ± 13.0 ± 7.8 ± 1.1 ± 2.8

Health

Placebo Group (n = 102)t 62.4 37.7 132.5 80.2 13.8 5.8 6.5 25.1 18.9

43.5 49.7 6.8

40.0 51.0 9.0

61.4 38.6

58.7 41.3

28.0 20.0

25.5 17.7

± 8.6 ± 14.4 ± 7.9 ± 1.3 ± 3.2

Study* P Value >0.2 > 0.2 > 0.2 >0.2 >0.2 > 0.2 0.03 > 0.2 >0.2 > 0.2

>0.2

> 0.2

* All risk factors were self-reported. t Plus-minus values are mean ± SE. t Participants with hypertension had a systolic blood pressure of 160 mm Hg or higher, or a diastolic blood pressure of 95 mm Hg or higher, or were currently being treated with antihypertensive medication. § Patients with high cholesterol levels had a cholesterol level of 6.7 mmol/L or higher, or were currently being treated for high cholesterol; this information was available for approximately 70% of participants. || In either parent before 60 years of age.

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Table 2. Confirmed Myocardial Infarctions, Strokes, and Deaths among 333 Participants with Chronic Stable Angina End Point

Aspirin Group (n = 178)

Placebo Group (n = 155)

0 7 832.5 7 7

4 16 704.7 20 20

1 4 820.4 11

0 0 750.2 2

0 6 849.6 7

4 7 758.0 11

Myocardial infarction Fatal Nonfatal Person-years of observation Total (age- and beta carotene-adjusted relative risk*) Total (multivariate relative riskt) Stroke Hemorrhagic Functionally important! Person-years of observation Total (age- and beta carotene-adjusted relative risk*) Death Acute infarction Cardiovascular Person-years of observation Total (age- and beta carotene-adjusted relative risk*)

P Value

Relative Risk

95% CI

0.37

0.16 to 0.84

0.019

0.30 0.13

0.14 to 0.63 0.04 to 0.42

0.003 < 0.001

5.37

1.30 to 22.1

0.02

0.75

0.25 to 2.33

> 0.2

0.51

0.18 to 1.51

> 0.2

* Adjustment for age (5-year categories) and beta carotene treatment assignment. t While simultaneously controlling for age (5-year categories), cigarette smoking (never, past, current), systolic and diastolic blood pressure, serum cholesterol level, diabetes mellitus (yes or no), parental history of infarction before 60 years of age (yes or no), body mass index, alcohol intake (> daily or rarely or never), vigorous exercise (> once per week or < once per week), and beta carotene assignment. $ Includes stroke that impairs function at time of discharge.

myocardial infarction was attributable to aspirin therapy (multivariate relative risk, 0.13; CI, 0.04 to 0.42; P < 0.001). Of 13 confirmed strokes, 11 were in the aspirin group and 2 were in the placebo group (age- and beta carotene-adjusted relative risk, 5.37; CI, 1.3 to 22.1; P = 0.02). None was fatal, but 4 produced some long-term functional impairment. One hemorrhagic stroke, in the aspirin group, was not associated with any long-term impairment. Compared with participants with chronic stable angina who did not have a stroke, the 13 participants with strokes tended to have, on average, higher systolic and diastolic blood pressures, increased body mass indices, and higher rates of current smoking and diabetes. One stroke, in the aspirin group, occurred after an invasive vascular procedure. Of the 333 participants, a total of 18 died. Seven had received aspirin and 11 had received placebo (age- and beta carotene-adjusted relative risk, 0.51; CI, 0.18 to 1.51; P > 0.2). Of 13 cardiovascular deaths (72% of all fatalities), 6 were among participants receiving aspirin and 7 were among participants receiving placebo (ageand beta carotene-adjusted relative risk, 0.75; CI, 0.25 to 2.33; P > 0.2). Four cardiovascular deaths were classified as resulting from acute myocardial infarction; all were among participants receiving placebo. To assess whether the observed reduction in the risk for myocardial infarction was present among participants with chronic stable angina and without previous coronary bypass surgery or coronary angioplasty, a subgroup analysis was done among the 221 participants who had not had these procedures at the time of randomization. In this subgroup, 20 myocardial infarctions occurred, 5 among those receiving aspirin and 15 among those receiving placebo (age- and beta carotene-adjusted relative risk, 0.27; CI, 0.11 to 0.66; P = 0.007) (Table 3). While simultaneously controlling for other cardiovascular risk factors, an overall 86% reduction in

the risk for first myocardial infarction was found to be attributable to aspirin. This finding was virtually identical to that of the primary intention-to-treat analysis (multivariate relative risk, 0.14; CI, 0.04 to 0.56; P = 0.005). Discussion These data show a significant 87% reduction in the risk for first myocardial infarction among patients with chronic stable angina who were randomly assigned to receive alternate-day, low-dose aspirin therapy and who were followed for 60.2 months (P < 0.001). This reduction in the risk for first myocardial infarction was found in all patients with chronic stable angina, including those with and those without previous coronary revascularization. In this group of patients, the risk for stroke also was apparently increased. This finding, however, should be viewed in the context of the totality of evidence about aspirin and cerebrovascular disease, which indicates that aspirin reduces the risk for thrombotic stroke. Specifically, several large trials of secondary prevention in the United States (19), Canada (20), and the United Kingdom (21) have shown reductions in the risk for cerebrovascular disease in patients who were randomly assigned to aspirin therapy. Further, a conclusive 22% reduction in the risk for subsequent stroke has been shown in a recent overview of all trials of antiplatelet therapy in patients with previous cerebrovascular disease, trials that included more than 10 000 randomly assigned patients and 750 stroke events (14). In addition, in the Second International Study of Infarct Survival (ISIS-2), low-dose aspirin therapy given for suspected evolving myocardial infarction yielded a 46% reduction in the overall risk for stroke (47 events with aspirin as compared with 81 events with placebo; P = 0.003) (15). Finally, the placebo arm of the recent

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Table 3. Confirmed Myocardial Infarctions among 221 Participants with Chronic Stable Angina without Previous Coronary Revascularization Myocardial Infarction

Aspirin Group (n = 119)

Placebo Group (n = 102)

Relative Risk

95% CI

P Value

2 13 15 15 451.8

0.33 0.27 0.14

0.13 to 0.82 0.11 to 0.66 0.04 to 0.56

0.025 0.007 0.005

n Fatal Nonfatal Total (age- and beta carotene-adjusted relative risk*) Total (multivariate relative riskt) Person-years of observation

0 5 5 5 552.1

* Adjusted for age (5-year categories) and beta carotene treatment assignment. t While simultaneously controlling for age (5-year categories), cigarette smoking (never, past, current), systolic and diastolic blood pressure, serum cholesterol level, diabetes mellitus (yes or no), parental history of infarction before 60 years of age (yes or no), body mass index, alcohol intake (> daily or rarely or never), vigorous exercise (> once per week or < once per week), and beta carotene assignment.

Stroke Prevention in Atrial Fibrillation trial was terminated early, because an extreme benefit of antiplatelet and anticoagulant therapy was found among high-risk patients (22). Symptomatic coronary artery disease often progresses from the stage of chronic stable angina to unstable angina and then to myocardial infarction. Aspirin therapy effectively prevents myocardial infarction among patients in the latter stages of this progression (23, 24). For the many patients whose disease is at the stage of chronic stable angina, but who have not had infarction, aspirin therapy may be useful in the primary prevention of myocardial infarction. These data, indicating that alternate-day, low-dose aspirin therapy substantially reduces the risk for first myocardial infarction for patients with chronic stable angina, provide relevant clinical information about the management of this syndrome. No previous clinical trial has described the effect of antiplatelet therapy for the primary prevention of first myocardial infarction among patients with chronic stable angina. Several earlier trials of aspirin, sulfinpyrazone, or dipyridamole have, however, examined this issue among patients with previous myocardial infarction (25-35). In the Anturane Reinfarction Italian Study (31) and the German-Austrian Myocardial Infarction Study (32), patients with stable angina after their first infarction were not at statistically significant higher risk for reinfarction than were those in the general study group. In both these trials, however, the sample sizes were small and follow-up lasted less than 2 years. In the Aspirin Myocardial Infarction Study (33), a higher 3-year mortality was found for patients with angina after infarction, but no statistically significant difference was found between the treatment groups. In the Coronary Drug Project Aspirin trial (34), half of all patients had angina at the time of randomization, but this characteristic did not significantly change estimates of mortality between treatment groups. Finally, in the Second Persantine Aspirin Reinfarction Study (35), a subgroup analysis of patients with angina did not show significant reductions in reinfarction and cardiovascular deaths. Although several previous trials of secondary prevention have raised the possibility that antiplatelet therapy is effective in patients with chronic stable angina after first infarction, none had a sufficient number of end points to test this hypothesis adequately. 838

The reduced incidence of first myocardial infarction among patients with chronic stable angina shown in this trial was unlikely to have resulted from an effect of aspirin on atherosclerotic progression or regression. Our data did not support the hypothesis that aspirin therapy reduced atherosclerotic progression in apparently healthy men (36), and, in another study, aspirin therapy did not lead to the regression of angiographically documented coronary disease (37). Low-dose aspirin therapy seems more likely to prevent myocardial infarction by inhibiting platelet aggregation, particularly during high-risk periods of the day (38). Although aspirin clearly reduces the incidence of first myocardial infarction, concern about the adverse effects of longterm therapy has led to the development of thromboxane-specific antagonists. To date, however, none of these agents has been shown to have a clinically important antithrombotic effect (39). On the basis of the available evidence, the decision of whether to prescribe aspirin for patients with chronic stable angina should be made on an individual basis, balancing the cardiovascular risk profile of the patient, the side effects of the drug, and the observed benefits of the risk for first myocardial infarction. For primary prevention, a recent overview (40) of all 27 210 participants enrolled in the American and British trials has shown a 32% overall reduction in nonfatal myocardial infarction (P < 0.001). Although based on an inadequate number of events, this overview found an apparent, but nonstatistically significant, increase in the risk for stroke and small and nonstatistically significant decreases in total and cardiovascular mortality. For a given patient, a first infarction is typically associated with a 20% mortality before hospitalization and an 8% to 15% in-hospital mortality (41-43). The clear benefit of aspirin in reducing the risk for first myocardial infarction in patients with chronic stable angina must be balanced against the potential adverse effects associated with aspirin therapy. For patients with chronic stable angina, the absolute risk for myocardial infarction is high. Further information clearly is needed to guide this decisionmaking process, particularly for women for whom no randomized data about primary prevention are yet available. Acknowledgments: The authors thank the Steering Committee and staff of the Physicians' Health Study and the 22 071 physicians participating in the trial.

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Grant Support: By grants HL-26490, HL-34595, CA-34944, and CA40360 from the National Institutes of Health. Dr. Ridker is supported by training grant HL-07575 from the National Heart, Lung, and Blood Institute. Requests for Reprints: Paul M. Ridker, MD, Brigham and Women's Hospital, 55 Pond Avenue, Brookline, MA 02146. Current Author Addresses: Drs. Ridker and Gaziano: Division of Cardiology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Drs. Manson, Buring, and Hennekens: Departments of Medicine and Preventive Medicine, Brigham and Women's Hospital, 55 Pond Avenue, Brookline, MA 02146. References 1. Rosenberg HM, Klebba AJ. Trends in cardiovascular mortality with a focus on ischemic heart disease: United States, 1950-1976. In: Feinleib M, Havlik RJ, Thorn T, eds. Proceedings of the Conference on the Decline in Coronary Heart Disease Mortality. Bethesda, Maryland: National Institutes of Health; 1978:11-41: DHEW publication no. (NIH) 79-1610. 2. Harper RW, Kennedy G, DeSanctis RW, Hutter AM Jr. The incidence and pattern of angina prior to acute myocardial infarction: a study of 577 cases. Am Heart J. 1979;97:178-83. 3. Kent KM, Rosing DR, Ewels CJ, Lipson L, Bonow R, Epstein SE. Prognosis of asymptomatic and mildly symptomatic patients with coronary heart disease. Am J Cardiol. 1982;49:1823-31. 4. Frishman WH. Pharmacology of nitrates in angina pectoris. Am J Cardiol. 1985;56:81-131. 5. Thadani U, Fung HL, Darke AC, Parker JO. Oral isosorbide dinitrate in the treatment of angina pectoris: dose-response relationship and duration of action during acute therapy. Circulation. 1980;62: 491-502. 6. Braunwald E, ed. International Symposium on Beta-Adrenergic Blockade: A New Era in Cardiovascular Medicine. New York: Excerpta Medica; 1978. 7. Prichard BN. B-Adrenoreceptor blocking drugs in angina pectoris. In: Avery GS, ed. Cardiovascular Drugs: B-Adrenoreceptor Blocking Drugs, v. 2. Baltimore: University Park Press; 1978:85-118. 8. Stone PH, Antman EM, Muller JE, Braunwald E. Calcium channel blocking agents in the treatment of cardiovascular disorders. Part II. Hemodynamic effects and clinical applications. Ann Intern Med. 1980;93:886-904. 9. Krickler DM. Calcium antagonists for chronic stable angina pectoris. Am J Cardiol. 1987;59:95B-100B. 10. Hopf R, Dowinsky S, Kaltenbach M. Use of calcium channel blocking agents in the treatment of classic exertional angina. In: Stone PH, Antman EM, eds. Calcium Channel Blocking Agents in the Treatment of Cardiovascular Disorders. Mount Kisco, New York: Futura Publishing Co.; 1983:241-68. 11. Roth GJ, Stanford N, Majerus PW. Acetylation of prostaglandin synthase by aspirin. Proc Natl Acad Sci U S A. 1975;72:3073-6. 12. Burch JW, Stanford N, Majerus PW. Inhibition of platelet prostaglandin synthetase by oral aspirin. J Clin Invest. 1978;61:314-9. 13. Hennekens CH, Buring JE, Sandercock P, Collins R, Peto R. Aspirin and other antiplatelet agents in the secondary and primary prevention of cardiovascular disease. Circulation. 1989;80:749-56. 14. Antiplatelet Trialists' Collaboration. Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J [Clin Res]. 1988;296:320-31. 15. Second International Study of Infarct Survival Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2:349-60. 16. Steering Committee of the Physicians' Health Study Research Group. Findings from the aspirin component of the ongoing Physicians' Health Study. N Engl J Med. 1988;318:262-4. 17. Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med. 1989;321:129-35. 18. World Health Organization. Ischaemic Heart Disease Registers: Report of the Fifth Working Group, including a second revision of the operating protocol, Copenhagen, 26-29 April 1971. Copenhagen: Regional Office for Europe, World Health Organization; 1971. 19. Fields WS, Lemak NA, Frankowski RF, Hardy RJ. Controlled trial of aspirin in cerebral ischemia. Stroke. 1977;8:301-14.

20. Canadian Cooperative Study Group. A randomized trial of aspirin and sulfinpyrazone in threatened stroke. N Engl J Med. 1978;299: 53-9. 21. UK TIA Study Group. United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: interim results. Br Med J [Clin Res]. 1988; 296:316-20. 22. Stroke Prevention in Atrial Fibrillation Study Group Investigators. Preliminary report of the Stroke Prevention in Atrial Fibrillation Study. N Engl J Med. 1990;322:863-8. 23. Lewis HD Jr, Davis JW, Archibald DG, et al. Protective effects of aspirin against myocardial infarction and death in men with unstable angina: results of a Veterans Administration cooperative study. N Engl J Med. 1983;309:396-403. 24. Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial. N Engl J Med. 1985;313:1369-75. 25. The Persantine-Aspirin Reinfarction Study Research Group. Persantine and aspirin in coronary heart disease. Circulation. 1980,62:44961. 26. Elwood PC, Sweetnam PM. Aspirin and secondary mortality after myocardial infarction. Lancet. 1979;2:1313-5. 27. Elwood PC, Cochrane AL, Burr ML, et al. A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction. Br Med J. 1974;1:436-40. 28. Anturane Reinfarction Trial Research Group. Sulfinpyrazone in the prevention of cardiac death after myocardial infarction. N Engl J Med. 1978;298:289-95. 29. Anturane Reinfarction Trial Research Group. Sulfinpyrazone in the prevention of sudden death after myocardial infarction. N Engl J Med. 1980;302:250-6. 30. Vogel G, Fischer C, Huyke R. Prevention of reinfarction with acetylsalicyclic acid. In: Breddin K, Loew D, Ueberla K, Dorndorf W, Marx R, eds. Prophylaxis of Venous, Peripheral, Cardiac, and Cerebral Vascular Diseases with Acetylsalicyclic Acid. Stuttgart: Schattauer; 1981:123-8. 31. Anturane Reinfarction Italian Study Group. Sulphinpyrazone in post-myocardial infarction. Lancet. 1982;1:237-42. 32. Breddin K, Loew D, Lechner K, Uberla K, Walter E. Secondary prevention of myocardial infarction. Comparison of acetylsalicylic acid, phenprocoumon, and placebo. Thromb Haemost. 1979;41:22536. 33. Aspirin Myocardial Infarction Study Research Group. A randomized, controlled trial of aspirin in persons recovered from myocardial infarction. JAMA. 1980;243:661-9. 34. The Coronary Drug Project Research Group. Aspirin in coronary heart disease. J Chronic Dis. 1976;29:625-42. 35. Klimt CR, Knatterud GL, Stamler J, Meier P. Persantine-Aspirin Reinfarction Study. Part II. Secondary coronary prevention with persantine and aspirin. J Am Coll Cardiol. 1986;7:251-69. 36. Ridker PM, Manson JE, Buring JE, Goldhaber SZ, Hennekens CH. The effect of chronic platelet inhibition on clinical characteristics of acute myocardial infarction in a randomized trial of physicians [Abstract]. Clin Res. 1990;38:291A. 37. Chesebro JH, Webster WI, Smith HC, et al. Antiplatelet therapy in coronary disease progression: reduced infarction and new lesion formation. Circulation. 1989;80(Suppl 2):266. 38. Ridker PM, Manson JE, Buring JE, Muller JE, Hennekens CH. Circadian variation of acute myocardial infarction and the effect of low-dose aspirin in a randomized trial of physicians. Circulation. 1990;82:897-902. 39. Fiddler GI, Lumley P. Preliminary clinical studies with thromboxane synthase inhibitors and thromboxane receptor blockers. A review. Circulation. 1990;81(Suppl l):I69-78. 40. Hennekens CH, Peto R, Hutchison GB, Doll R. An overview of the British and American aspirin studies [Letter]. N Engl J Med. 1988; 318:923-4. 41. Moss AJ, Benhorin J. Prognosis and management after a first myocardial infarction. N Engl J Med. 1990;322:743-53. 42. Thanavaro S, Krone RJ, Kleiger RE, et al. In-hospital prognosis of patients with first nontransmural and transmural infarctions. Circulation. 1980;61:29-33. 43. Kannel WB, Sorlie P, McNamara PM. Prognosis after initial myocardial infarction: the Framingham study. Am J Cardiol. 1979;44: 53-9.

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Low-dose aspirin therapy for chronic stable angina. A randomized, placebo-controlled clinical trial.

To evaluate the efficacy of low-dose aspirin in the primary prevention of myocardial infarction among patients with chronic stable angina...
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